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GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: A case report
Gynecologic Oncology 99 (2005) 764 – 766 www.elsevier.com/locate/ygyno
Case Report
GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: A case report L. Ameryckx*, H.M. Fatemi, P. De Sutter, J.J. Amy Department of Gynecology, Andrology and Obstetrics, Academisch Ziekenhuis-Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium Received 24 May 2005 Available online 19 August 2005
Abstract Background. Ovarian granulosa cell tumors (GCT) are usually treated by surgery and chemotherapy. Successful response to GnRH agonists as an adjuvant therapy has previously been reported. In this case of recurrent GCT, we used a GnRH antagonist. Case. A 78-year-old woman underwent surgery for an ovarian granulosa cell tumor (pT1a N0 Mx). Six months later, laparotomy revealed an inoperable recurrence of the tumor. Experimental treatment with a GnRH antagonist was not clearly successful. This is in contrast to the previously proven benefit of GnRH agonist therapy in this type of malignancy and to the positive response elicited by GnRH antagonists in epithelial ovarian tumors. Conclusion. GnRH antagonist therapy had no demonstrable efficacy in the treatment of a poorly differentiated and aggressive recurrent granulosa cell tumor. D 2005 Elsevier Inc. All rights reserved. Keywords: Granulosa cell tumor; GnRH antagonists; GnRH agonists
Introduction Granulosa cell tumors (GCT) are estrogen-producing neoplasms that account for less than 3% of all ovarian malignancies. Surgery is the cornerstone of treatment and is sufficient if the disease is confined to the ovary. GCT is a low-grade malignancy with favorable prognosis, but recurrences and extra ovarian spread may develop in up to 25% after a long interval. The optimal treatment for women with recurrent or metastatic disease is not established. Repeated surgical debulking and chemotherapy are most often resorted to. Current cancer research is focused on better understanding the biology of cancers, to inhibit the pathways that lead to uncontrolled cell growth. A lot of study these days is being done on gonadotropinreleasing hormone (GnRH) analogs. In several steroid
* Corresponding author. Fax: +32 2 477 6546. E-mail address: linda [email protected] (L. Ameryckx).
dependant malignancies, such as estrogen-dependant breast cancer and prostate cancer, GnRH analogs have been proven to be effective as an adjuvant treatment [1]. Recent studies revealed the existence GnRH receptors in ovarian cancers and subsequent anti-proliferative responses to GnRH analogs have been reported in in vitro and in vivo studies [2 – 6]. Two previous reports describe the effective response of GnRH agonist analog therapy on ovarian granulosa cell malignancy [7,8]. However, recent data showed an even more potent response of GnRH antagonists on ovarian malignant cell lines; therefore, we used this promising medication in the adjuvant treatment of a granulosa cell tumor recurrence [2,4].
Case report A 78-year-old woman was presented at the outpatients clinic with postmenopausal bleeding and breast tenderness. On transvaginal ultrasound and computed tomographic (CT) scan, a large adnexal mass (15 15 cm) with several cystic
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.07.007
YGYNO-971155; No of pages: 3; 4C:
L. Ameryckx et al. / Gynecologic Oncology 99 (2005) 764 – 766
and solid compartments, was visualized. High estradiol (190 ng/l) and inhibin B levels (1038 ng/l), together with hyperplasia of the endometrium seen on ultrasound, raised the suspicion of an estrogen-producing granulosa cell tumor. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy and omentectomy. We removed a 1495-g solid-cystic tumor of the right ovary. A grade 3, poorly differentiated granulosa cell tumor (15 20 11 cm) (pT1 N0 Mx) was confirmed by the histological examination. The mitotic rate of the tumor was high (>5 mitoses/10 HPF). The histology report described a Fmoire silk pattern_ with areas of micro- and macro-follicles consistent with a mixed Ftrabeculoid– folliculoid_ subtype. No sarcoma components were identified. Inhibin A immunohistochemistry of the tumor stained weakly positive. Estrogen and progesterone receptors were negative. As the tumor was confined to the right ovary only (stage Ia) and because of the advanced age and poor general condition of the patient, it was decided not to give her adjuvant chemotherapy. Six months after surgery, she was readmitted for small bowel obstruction. At laparotomy, extensive peritoneal carcinomatosis and a retroperitoneal mass with a diameter of 20 cm was seen. The tumor was found to be inoperable. Adhesiolysis was performed and a fragment (6 4 1 cm) of it was removed for histological examination. The CT scan suggested the existence of liver metastases. After the operation the bowel function resumed. The prognosis was poor and the patient refused adjuvant chemotherapy. GnRH analogs cause only discrete systemic side effects and are easy to administer, after informed consent, the patient agreed to submit to this experimental treatment. Ganirelix 0.25 mg (Orgalutran\, Organon, Belgium) was given daily subcutaneously by starting 8 days after surgery, for about 1 month. At initiation of treatment, the patient’s estradiol and inhibin A levels decreased markedly from 265 ng/l to 104 ng/l. The response however lasted only several days. Two weeks later, estradiol and inhibin A levels rose again above the pre-operative levels. A CT scan showed an enlargement of the abdominal mass.
Comment Two classes of GnRH analogs are currently available: GnRH agonists and antagonists. Especially GnRH agonists are widely and successfully used in the management of hormone-dependent malignancies [1]. Chronic administration results in down regulation and desensitization of pituitary GnRH receptors, leading to complete suppression of ovarian estrogen production. Beside this indirect hormonal effect mediated by the suppression of gonadal steroidogenesis, GnRH analogs also exert a more local effect, on the tumor itself. Approximately
765
80% of ovarian epithelial tumors express GnRH and its receptor. The latter are thought to act as part of an autocrine regulatory system. Stimulation of the receptor by GnRH or its analog activates a number of intracellular signaling mechanisms, which seems to reduce tumor cell proliferation [2 –4]. Interestingly, GnRH antagonists display an activity at tumor receptor level similar to that of the agonists. This indicates that the dichotomy GnRH agonist –GnRH antagonist prevailing in the pituitary is not valid for the tumor GnRH system [2,3]. Two types of GnRH receptors have been identified in human ovarian cancers. Type I and type II GnRH receptors. In vitro studies have shown that the anti-proliferative activity transmitted by the second type of GnRH receptor is significantly stronger than that of the GnRH-I receptor [3]. GnRH antagonists have agonistic effects on this type II receptor and show stronger anti-tumoral effects in in vivo animal models than agonists [4]. A phase II clinical trial performed by Emons et al. has given remarkable results. They administered the antagonist cetrorelix in patients with ovarian epithelial carcinoma refractory to platinum chemotherapy and showed that 18% of the patients treated obtained partial remission and 35% experienced disease stabilization for up to 1 year [5]. Our patient presented with a recurrence of a granulosa cell tumor, which is a neoplasm of stromal origin. An autocrine/paracrine function of GnRH possibly exists in granulosa cells [6]. It is probable that such GnRH-based autocrine systems are also present in malignant granulosa cells. Seen the encouraging anti-cancer activity of LHRH receptor antagonists in epithelian ovarian tumors, and the fact that GnRH agonist therapy has proven some efficacy in advanced granulosa cell malignancies [7,8], we treated the patient with Ganirelix, a GnRH antagonist. We assumed that GnRH antagonists would have a similar and maybe even a more pronounced anti-tumor effect in this kind of malignancy. In the initial phase of treatment with the GnRH antagonist, the decreasing estradiol and inhibin A levels were very promising. Inhibin is a peptide hormone produced by ovarian granulosa cells during the follicular phase of the normal menstrual cycle. It is undetectable in the serum of postmenopausal women and can be used as a marker for the size of a granulosa cell tumor and thus as a marker for primary as well as recurrent disease. The fall in estradiol and inhibin A levels could have been caused by the removal of a fragment of tumor for histological examination. Yet, in regard to the extent of the growth, only a small part of it had been removed. As the estradiol and inhibin A levels had decreased markedly, this might have been due to an initial/transient response to the GnRH antagonist treatment. To our knowledge, this is the first description of the use of a GnRH antagonist in the treatment of an ovarian
766
L. Ameryckx et al. / Gynecologic Oncology 99 (2005) 764 – 766
granulosa cell tumor. Previous trials of agonists for the treatment of this type of tumor have given promising results, and research concerning tumor receptor level indicates that GnRH antagonist therapy might have a beneficial effect. However, this antagonist treatment was ineffective in our patient who had a fast growing and poorly differentiated tumor. The extremely rapid and excessive recurrence of a pT1a GCT, however, is fairly atypical for this tumor entity. Generally, these neoplasms have an indolent growth pattern and a tendency for late recurrence. Long-term disease-free survival rates for women with stage I disease are 75– 90%. The median time to relapse is 4 –6 years but recurrences are associated with a high mortality rate. The prognosis of GCT of the ovary largely depends upon surgical stage of disease at the time of diagnosis. In stage I disease, factors such as patient age, tumor size, mitotic index and tumor rupture have also been reported to be of prognostic importance [9,10]. Despite the fact that this was a stage Ia GCT, our patient had several negative prognostic elements: advanced age, large tumor size and high mitotic index. These factors may have contributed to the early recurrence. The fact that this tumor was too advanced and aggressive might be a reason for the poor response to the antagonist therapy. Therefore, no definite conclusions on the failure of this treatment can be drawn. Clinical trials, similar to the one Emons did with epithelial tumors, are warranted.
References [1] Jonat W. The role of LHRH analogs in premenopausal breast cancer. In: Lunenfeld B, editor. GnRH Analogs, the State of the Art. New York’ Parthenon Publishing Group; 2001. p. 127 – 34. [2] Emons G, Ortmann O, Schulz KD, Schally AV. Growth-inhibitory actions of analogs of luteinizing hormone releasing hormone on tumor cells. Trends Endocrinol Metab 1997;8:155 – 362. [3] Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotrophin-releasing hormone II receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. J Clin Endocrinol Metab 2002;87:1427 – 30. [4] Grundker C, Gunthert AR, Westphalen, Emons G. Biology of the gonadotrophin-releasing hormone system in gynaecological cancers. Eur J Endocrinol 2002;146:1 – 14. [5] Emons G, Grundker C. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr-Relat Cancer 2003;10: 291 – 9. [6] Minaretzis D, Jakubowski M, Mortola JF, Pavlou SN. Gonadotrophinreleasing hormone receptor gene expression in human ovary and granulosa lutein cells. J Clin Endocrinol Metab 1995;80:430 – 4. [7] Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A. Gonadotrophin releasing hormone agonist analogue therapy effective in ovarian granulosa cell malignancy. Gynecol Oncol 1989;35(3):406 – 8. [8] Kauppila A, Bangah M, Burger H, Martikainen H. GnRH agonist analog therapy in advanced/recurrent granulosa cell tumors: further evidence of a role of inhibin in monitoring response to treatment. Gynecol Endocrinol 1992;6(4):271 – 4. [9] Malmstrom H, Hogberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 1994;52(1):50 – 5. [10] Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;15(21(6)):1180 – 9.
Case Report
GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: A case report L. Ameryckx*, H.M. Fatemi, P. De Sutter, J.J. Amy Department of Gynecology, Andrology and Obstetrics, Academisch Ziekenhuis-Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium Received 24 May 2005 Available online 19 August 2005
Abstract Background. Ovarian granulosa cell tumors (GCT) are usually treated by surgery and chemotherapy. Successful response to GnRH agonists as an adjuvant therapy has previously been reported. In this case of recurrent GCT, we used a GnRH antagonist. Case. A 78-year-old woman underwent surgery for an ovarian granulosa cell tumor (pT1a N0 Mx). Six months later, laparotomy revealed an inoperable recurrence of the tumor. Experimental treatment with a GnRH antagonist was not clearly successful. This is in contrast to the previously proven benefit of GnRH agonist therapy in this type of malignancy and to the positive response elicited by GnRH antagonists in epithelial ovarian tumors. Conclusion. GnRH antagonist therapy had no demonstrable efficacy in the treatment of a poorly differentiated and aggressive recurrent granulosa cell tumor. D 2005 Elsevier Inc. All rights reserved. Keywords: Granulosa cell tumor; GnRH antagonists; GnRH agonists
Introduction Granulosa cell tumors (GCT) are estrogen-producing neoplasms that account for less than 3% of all ovarian malignancies. Surgery is the cornerstone of treatment and is sufficient if the disease is confined to the ovary. GCT is a low-grade malignancy with favorable prognosis, but recurrences and extra ovarian spread may develop in up to 25% after a long interval. The optimal treatment for women with recurrent or metastatic disease is not established. Repeated surgical debulking and chemotherapy are most often resorted to. Current cancer research is focused on better understanding the biology of cancers, to inhibit the pathways that lead to uncontrolled cell growth. A lot of study these days is being done on gonadotropinreleasing hormone (GnRH) analogs. In several steroid
* Corresponding author. Fax: +32 2 477 6546. E-mail address: linda [email protected] (L. Ameryckx).
dependant malignancies, such as estrogen-dependant breast cancer and prostate cancer, GnRH analogs have been proven to be effective as an adjuvant treatment [1]. Recent studies revealed the existence GnRH receptors in ovarian cancers and subsequent anti-proliferative responses to GnRH analogs have been reported in in vitro and in vivo studies [2 – 6]. Two previous reports describe the effective response of GnRH agonist analog therapy on ovarian granulosa cell malignancy [7,8]. However, recent data showed an even more potent response of GnRH antagonists on ovarian malignant cell lines; therefore, we used this promising medication in the adjuvant treatment of a granulosa cell tumor recurrence [2,4].
Case report A 78-year-old woman was presented at the outpatients clinic with postmenopausal bleeding and breast tenderness. On transvaginal ultrasound and computed tomographic (CT) scan, a large adnexal mass (15 15 cm) with several cystic
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.07.007
YGYNO-971155; No of pages: 3; 4C:
L. Ameryckx et al. / Gynecologic Oncology 99 (2005) 764 – 766
and solid compartments, was visualized. High estradiol (190 ng/l) and inhibin B levels (1038 ng/l), together with hyperplasia of the endometrium seen on ultrasound, raised the suspicion of an estrogen-producing granulosa cell tumor. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy and omentectomy. We removed a 1495-g solid-cystic tumor of the right ovary. A grade 3, poorly differentiated granulosa cell tumor (15 20 11 cm) (pT1 N0 Mx) was confirmed by the histological examination. The mitotic rate of the tumor was high (>5 mitoses/10 HPF). The histology report described a Fmoire silk pattern_ with areas of micro- and macro-follicles consistent with a mixed Ftrabeculoid– folliculoid_ subtype. No sarcoma components were identified. Inhibin A immunohistochemistry of the tumor stained weakly positive. Estrogen and progesterone receptors were negative. As the tumor was confined to the right ovary only (stage Ia) and because of the advanced age and poor general condition of the patient, it was decided not to give her adjuvant chemotherapy. Six months after surgery, she was readmitted for small bowel obstruction. At laparotomy, extensive peritoneal carcinomatosis and a retroperitoneal mass with a diameter of 20 cm was seen. The tumor was found to be inoperable. Adhesiolysis was performed and a fragment (6 4 1 cm) of it was removed for histological examination. The CT scan suggested the existence of liver metastases. After the operation the bowel function resumed. The prognosis was poor and the patient refused adjuvant chemotherapy. GnRH analogs cause only discrete systemic side effects and are easy to administer, after informed consent, the patient agreed to submit to this experimental treatment. Ganirelix 0.25 mg (Orgalutran\, Organon, Belgium) was given daily subcutaneously by starting 8 days after surgery, for about 1 month. At initiation of treatment, the patient’s estradiol and inhibin A levels decreased markedly from 265 ng/l to 104 ng/l. The response however lasted only several days. Two weeks later, estradiol and inhibin A levels rose again above the pre-operative levels. A CT scan showed an enlargement of the abdominal mass.
Comment Two classes of GnRH analogs are currently available: GnRH agonists and antagonists. Especially GnRH agonists are widely and successfully used in the management of hormone-dependent malignancies [1]. Chronic administration results in down regulation and desensitization of pituitary GnRH receptors, leading to complete suppression of ovarian estrogen production. Beside this indirect hormonal effect mediated by the suppression of gonadal steroidogenesis, GnRH analogs also exert a more local effect, on the tumor itself. Approximately
765
80% of ovarian epithelial tumors express GnRH and its receptor. The latter are thought to act as part of an autocrine regulatory system. Stimulation of the receptor by GnRH or its analog activates a number of intracellular signaling mechanisms, which seems to reduce tumor cell proliferation [2 –4]. Interestingly, GnRH antagonists display an activity at tumor receptor level similar to that of the agonists. This indicates that the dichotomy GnRH agonist –GnRH antagonist prevailing in the pituitary is not valid for the tumor GnRH system [2,3]. Two types of GnRH receptors have been identified in human ovarian cancers. Type I and type II GnRH receptors. In vitro studies have shown that the anti-proliferative activity transmitted by the second type of GnRH receptor is significantly stronger than that of the GnRH-I receptor [3]. GnRH antagonists have agonistic effects on this type II receptor and show stronger anti-tumoral effects in in vivo animal models than agonists [4]. A phase II clinical trial performed by Emons et al. has given remarkable results. They administered the antagonist cetrorelix in patients with ovarian epithelial carcinoma refractory to platinum chemotherapy and showed that 18% of the patients treated obtained partial remission and 35% experienced disease stabilization for up to 1 year [5]. Our patient presented with a recurrence of a granulosa cell tumor, which is a neoplasm of stromal origin. An autocrine/paracrine function of GnRH possibly exists in granulosa cells [6]. It is probable that such GnRH-based autocrine systems are also present in malignant granulosa cells. Seen the encouraging anti-cancer activity of LHRH receptor antagonists in epithelian ovarian tumors, and the fact that GnRH agonist therapy has proven some efficacy in advanced granulosa cell malignancies [7,8], we treated the patient with Ganirelix, a GnRH antagonist. We assumed that GnRH antagonists would have a similar and maybe even a more pronounced anti-tumor effect in this kind of malignancy. In the initial phase of treatment with the GnRH antagonist, the decreasing estradiol and inhibin A levels were very promising. Inhibin is a peptide hormone produced by ovarian granulosa cells during the follicular phase of the normal menstrual cycle. It is undetectable in the serum of postmenopausal women and can be used as a marker for the size of a granulosa cell tumor and thus as a marker for primary as well as recurrent disease. The fall in estradiol and inhibin A levels could have been caused by the removal of a fragment of tumor for histological examination. Yet, in regard to the extent of the growth, only a small part of it had been removed. As the estradiol and inhibin A levels had decreased markedly, this might have been due to an initial/transient response to the GnRH antagonist treatment. To our knowledge, this is the first description of the use of a GnRH antagonist in the treatment of an ovarian
766
L. Ameryckx et al. / Gynecologic Oncology 99 (2005) 764 – 766
granulosa cell tumor. Previous trials of agonists for the treatment of this type of tumor have given promising results, and research concerning tumor receptor level indicates that GnRH antagonist therapy might have a beneficial effect. However, this antagonist treatment was ineffective in our patient who had a fast growing and poorly differentiated tumor. The extremely rapid and excessive recurrence of a pT1a GCT, however, is fairly atypical for this tumor entity. Generally, these neoplasms have an indolent growth pattern and a tendency for late recurrence. Long-term disease-free survival rates for women with stage I disease are 75– 90%. The median time to relapse is 4 –6 years but recurrences are associated with a high mortality rate. The prognosis of GCT of the ovary largely depends upon surgical stage of disease at the time of diagnosis. In stage I disease, factors such as patient age, tumor size, mitotic index and tumor rupture have also been reported to be of prognostic importance [9,10]. Despite the fact that this was a stage Ia GCT, our patient had several negative prognostic elements: advanced age, large tumor size and high mitotic index. These factors may have contributed to the early recurrence. The fact that this tumor was too advanced and aggressive might be a reason for the poor response to the antagonist therapy. Therefore, no definite conclusions on the failure of this treatment can be drawn. Clinical trials, similar to the one Emons did with epithelial tumors, are warranted.
References [1] Jonat W. The role of LHRH analogs in premenopausal breast cancer. In: Lunenfeld B, editor. GnRH Analogs, the State of the Art. New York’ Parthenon Publishing Group; 2001. p. 127 – 34. [2] Emons G, Ortmann O, Schulz KD, Schally AV. Growth-inhibitory actions of analogs of luteinizing hormone releasing hormone on tumor cells. Trends Endocrinol Metab 1997;8:155 – 362. [3] Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotrophin-releasing hormone II receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. J Clin Endocrinol Metab 2002;87:1427 – 30. [4] Grundker C, Gunthert AR, Westphalen, Emons G. Biology of the gonadotrophin-releasing hormone system in gynaecological cancers. Eur J Endocrinol 2002;146:1 – 14. [5] Emons G, Grundker C. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr-Relat Cancer 2003;10: 291 – 9. [6] Minaretzis D, Jakubowski M, Mortola JF, Pavlou SN. Gonadotrophinreleasing hormone receptor gene expression in human ovary and granulosa lutein cells. J Clin Endocrinol Metab 1995;80:430 – 4. [7] Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A. Gonadotrophin releasing hormone agonist analogue therapy effective in ovarian granulosa cell malignancy. Gynecol Oncol 1989;35(3):406 – 8. [8] Kauppila A, Bangah M, Burger H, Martikainen H. GnRH agonist analog therapy in advanced/recurrent granulosa cell tumors: further evidence of a role of inhibin in monitoring response to treatment. Gynecol Endocrinol 1992;6(4):271 – 4. [9] Malmstrom H, Hogberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 1994;52(1):50 – 5. [10] Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;15(21(6)):1180 – 9.